Clean, high-yield preparation of S,S and R,S amino acid isosteres

ABSTRACT

The present invention provides compounds and methods that can be used to convert the intermmediate halomethyl ketones (HMKs), e.g., chloromethyl ketones, to the corresponding S,S- and R,S-diastereomers. More particularly, the present invention provides: (1) reduction methods; (2) inversion methods; and (3) methods involving the epoxidation of alkenes. Using the various methods of the present invention, the R,S-epoxide and the intermediary compounds can be prepared reliably, in high yields and in high purity.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional PatentApplication Serial No. 60/132,278, filed May 3, 1999, which isincorporated herein by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

[0002] Human immunodeficiency virus (HIV), the causative agent ofacquired immunodeficiency syndrome (AIDS), encodes three enzymes,including the well-characterized proteinase belonging to the asparticproteinase family, the HIV protease. Inhibition of this enzyme has beenregarded as a promising approach for treating AIDS. Hydroxyethylamineisosteres have been extensively utilized in the synthesis of potent andselective HIV protease inhibitors. However, this modern generation ofHIV protease inhibitors has created an interesting challenge for thesynthetic organic chemist. Advanced x-ray structural analysis hasallowed for the design of molecules that fit closely into active siteson enzymes creating very effective drug molecules. Unfortunately, thesemolecules, designed by molecular shape, are often difficult to produceusing conventional chemistry.

[0003] The modern generation of HIV inhibitors has structuralsimilarities in a central three-carbon piece containing two chiralcarbons that link two larger groups on each side (see, e.g., Parkes, etal., J. Org. Chem. 1994 39, 3656). Numerous synthetic routes to theseisosteres have been developed. As illustrated below, a common strategyto prepare the linking group starts with an amino acid, such asphenylalanine, to set the chirality of the first carbon. Then, thelinking group is completed by a series of reactions including aone-carbon homologization during which the old amino acid carbon istransformed into a hydroxy-functionalized carbon having the correctchirality. However, the commercial production of isosteres by thismethod presents serious challenges, generally requiring low-temperatureorganometallic reactions (Baragua, et al., J. Org. Chem. 1997, 62, 6080)or the use of exotic reagents.

[0004] A second approach, which is illustrated below, is to convert theamino acid to an aldehyde and to add the carbon by use of a Wittigreaction to give an olefin (see, Luly, et al., J. Org. Chem. 1987, 52,1487). The olefin is then epoxidized. Alternatively, the aldehyde can bereacted with nitromethane, cyanide (see, Shibata, et al., Chem. Pharm.Bull. 1998, 46, 733) or carbene sources (see, Liu, et al., Org. Proc.Res. Dev. 1997, 1, 45). Instability and difficulty in preparation of thealdehyde make these routes undesirable (see, Beaulieu, et al., J. Org.Chem. 1997, 62, 3440).

[0005] Other routes that have been published, but not commercialized areillustrated in FIG. 1.

[0006] One of the best reagents that can be used to add a single carbonto amino acids is diazomethane because it gives high yields and fewside-products. In addition, diazomethane reactions are very clean,generating only nitrogen as a by-product. HIV inhibitor molecules needhigh purity because of the high daily doses required. As such,diazomethane is an ideal reagent for making high purity compounds. Inspite of the documented hazards of diazomethane, processes have recentlybeen developed that permit the commercial scale use of diazomethane toconvert amino acids to the homologous chloromethyl ketones (see, U.S.Pat. No. 5,817,778, which issued to Archibald, et al. on Oct. 6, 1998;and U.S. Pat. No. 5,854,405, which issued to Archibald, et al. on Dec.29, 1998). FIG. 2 illustrates examples of HIV protease inhibitorswherein the central linking group can be synthesized by the commercialuse of diazomethane. FIG. 3 illustrates a general reaction scheme thatcan be used to prepare the S,S-epoxide compound using diazomethane.

[0007] The most useful amino acid isosteres are based on phenylanaline.The key intermmediate in the synthesis of Sequinivir® (Roche) andAprenavir® (Glaxo Wellcome) is the(S,S-)N-t-butoxycarbonyl-1,2-epoxy-4-phenyl-3-butanamine. Several otherprotease inhibitors, such as those described in Chem, et al. (J. Med.Chem. 1996, 39, 1991) or those under development (e.g., BMS-234475 orBMS-232623), use the diastereomeric(R,S-)N-t-butoxycarbonyl-1,2-epoxy-4-phenyl-3-butanamine.

[0008] Beginning with readily available (L)-phenylanaline, one is ableto manufacture N-t-butoxycarbonyl-1-chloro-2-keto-4-phenylbutanamine(called “chloroketone” or “CMK”) using the methods described in theliterature (see, e.g., Parkes, et al., J. Org. Chem. 1994 39, 3656;Shaw, E., Methods in Enzymology (Academic Press, New York, London),1967, 11, 677; and Dufour, et al., J. Chem. Soc. Perkin Trans. I 1986,1895, the teachings of which are incorporated herein by reference).However, what are needed in the art are methods that allow one toproduce reliably and in high-yields either diastereomer, i.e., the S,Sor the R,S, from the common chloroketone starting material (see, FIG.4). Quite surprisingly, the present invention fulfills this and otherneeds.

SUMMARY OF THE INVENTION

[0009] The present invention provides compounds and methods that can beused to convert the intermmediate halomethyl ketones (HMKs), e.g.,chloromethyl ketones, to the corresponding S,S- and R,S-diastereomers.It is these chiral centers that determine the chiral centers in the HIVprotease inhibitor and, thus, the efficacy of the drug. As explainedherein, the present invention provides (1) reduction methods; (2)inversion methods; and (3) methods for preparing alkenes that, in turn,can undergo epoxidation reactions to form the desired R,S-epoxide. Usingthe various methods of the present invention, the R,S-epoxide and theintermediary compounds can be prepared reliably, in high yields and inhigh purity.

[0010] As such, in one embodiment, the present invention provides amethod for selectively preparing an R,S-halomethyl alcohol (R,S-HMA)compound having the following general formula:

[0011] the method comprising: reducing a compound having the followinggeneral formula:

[0012] with a non-chelating, bulky reducing agent to form the R,S-HMAcompound. In the above formulae, R¹ is an amino acid side chain (e.g., abenzyl group, an S-phenyl group, an alkyl group and a para-nitrobenzenegroup, etc.); R² is a blocking or protecting group (e.g., Boc, Cbz, Moc,etc.); and X¹ is a leaving group (e.g., a halo group, such as chloro).In a presently preferred embodiment, the non-chelating, bulky reducingagent is a member selected from the group consisting of LATBH and STBH.In another presently preferred embodiment, the reduction is carried outin a solvent such as diethyl ether. Once formed, the R,S-HMA can bereacted with an alkali metal base to form an R,S-epoxide.

[0013] In another embodiment, the present invention provides a methodfor preparing an R,S-halomethyl alcohol (R,S-HMA) compound having thefollowing general formula:

[0014] the method comprising: reducing a halomethyl ketone (HMK)compound having the following general formula:

[0015] with a reducing agent selected from the group consisting ofsodium cyanoborohydride, cerium chloride/sodium borohydride,K-Selectride®, KS-Selectride® and (+)-Dip Chloride™ to form the R,S-HMAcompound. In this method, R¹ is an amino acid side chain; R² is ablocking group; and X¹is a leaving group. Again, once formed, theR,S-HMA can be reacted with an alkali metal base to form an R,S-epoxide.

[0016] In another aspect, the present invention provides inversionmethods that can be used to selectively prepare the R,S-epoxide. In oneembodiment of the inversion method, R,S-epoxide is prepared by a fourstep process. More particularly, in one embodiment of the inversionmethod, the present invention provides a method for preparing anR,S-epoxide having the following general formula:

[0017] the method comprising: (a) reducing a halomethyl ketone (HMK)compound having the following general formula:

[0018] with a reducing agent to form an S,S-halomethyl alcohol (S,S-HMA)compound having the following general formula:

[0019] (b) contacting the S,S-HMA compound of Formula II with a memberselected from the group consisting of arylsulfonyl halides andalkylsulfonyl halides in the presence of an amine to form anS,S-halomethyl sulfonyl (S,S-HMS) compound having the following generalformula:

[0020] (c) contacting the S,S-HMS compound of Formula III with anacetate in the presence of a phase transfer catalyst and water to forman R,S-halomethyl acetate (R,S-HMAc) compound having the followinggeneral formula:

[0021] and (d) contacting the R,S-HMAc compound of Formula IV with analkali metal base to form the R,S-epoxide. In the above formulae, R¹ isan amino acid side chain (e.g., a benzyl group, an S-phenyl group, analkyl group, a para-nitrobenzene group, etc.); R² is a blocking orprotecting group; X¹ is a leaving group (i.e., a halo group, such aschloro); R³ is a functional group including, but not limited to,arylsulfonyls and alkylsulfonyls (e.g., a mesyl group, a tosyl group, atriflate group, a nosyl group, etc.); and R⁴ is an acyl group derivedfrom the acetate (e.g., an acetyl group).

[0022] In another embodiment of the inversion method, the presentinvention provides a method for preparing an R,S-epoxide compound havingthe following general formula:

[0023] the method comprising: (a) contacting an S,S-halomethyl sulfonyl(S,S-HMS) compound having the following general formula:

[0024] with a carbamate-forming acetate to form a cyclic carbamate; and(b) contacting the cyclic carbamate with an alkali metal base to formthe R,S-epoxide. In the above formulae, R¹, R², R³ and X¹ are as definedabove. In a presently preferred embodiment, the carbamate-formingacetate is sodium trichloroacetate.

[0025] In yet another aspect, the present invention provides a methodfor preparing R,S-epoxide by the epoxidation of an alkene. Moreparticularly, the present invention provides a method for preparing analkene having the following general formula:

[0026] the method comprising: (a) contacting a compound having thefollowing general formula:

[0027] with a hydrohalo acid to form a compound having the followinggeneral formula:

[0028] (b) reducing a compound of Formula II with a reducing agent toform a compound having the following general formula:

[0029] and (c) dehalohydroxylating a compound of Formula III to form thealkene. In the above formulae, R¹, R², and X¹ are as defined above. Onceprepared, the alkene can be converted to the R,S-epoxide using, forexample, m-chloroperbenzoic acid.

[0030] Other features, objects and advantages of the invention and itspreferred embodiments will become apparent from the detailed descriptionwhich follows.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031]FIG. 1 illustrates various routes that can be used to prepare anR,S-epoxide. FIG. 1(A) illustrates a method described by Ng, et al.,Org. Proc. Res. Dev. 1997, 1, 46; and Beaulieu, et al., J. Org. Chem.1997, 62, 3441. FIG. 1(B) illustrates a method described by Parkes, etal. J. Org. Chem. 1994, 59, 3656.

[0032]FIG. 2 illustrates examples of HMV protease inhibitors where thecentral linking group can be synthesized by commercial use ofdiazomethane.

[0033]FIG. 3 illustrates a general reaction scheme that can be used toprepare the epoxide compound.

[0034]FIG. 4 illustrates the two diastereomers that can be formed fromthe common chloroketone starting material, i.e., S,S-epoxide andR,S-epoxide.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

[0035] The present invention provides various compounds and methods thatcan be used to prepare both reliable and in high yields eitherdiastereomer, i.e., the S,S- or the R,S-, from the common halomethylketone (e.g., chloromethyl ketone) starting material. More particularly,as explained herein in greater detail, the present invention provides(1) reduction methods; (2) inversion methods, and (3) methods involvingthe epoxidation of alkenes.

[0036] A. The Reduction Methods

[0037] A variety of reducing agents can be used to reduce a halomethylketone (HMK) to a halomethyl alcohol (HMA) (see, Table I). However,under most conditions, the predominate diastereomer is the 2S,3S-HMA.For instance, reduction of HMK with sodium borohydride in ethanol (Chen,et al., J. Med. Chem. 1996, 39, 1991) produces a 1:4 mixture of R,S:S,SHMA in near quantitative yield. Moreover, the reduction of HMK withaluminium isopropoxide in isopropanol can give ratios as high as 1:18 infavor of the S,S-isomer (see, U.S. Pat. Nos. 5,684,176 and 5,847,144,both of which issued to Hilpert). Thus, commercial routes to S,S-HMA areeasily achieved.

[0038] In contrast, the preparation of the R,S-isomer is much moredifficult. A slight increase in the R,S-HMA:S,S-HMA ratio is achievedwhen the reaction solvent, ethanol, is replaced with THF. Furtherenhancement in the R,S-HMA:S,S-HMA ratio is obtained when the reductionis carried out in the presence of CeCl₃ (Barluenga, J. Org. Chem. 1997,62,5974); but even then the ratio of R,S-HMA:S,S-HMA is <1:1. Otherreducing agents, such as LiAlH4, sodium cyanoborohydride, potassiumborohydride, etc., under a variety of reaction conditions, also fail toprovide >1:1 R,S-HMA:S,S-HMA. In fact, a perusal of the literaturesupports the observation that S,S-HMA is the preferred isomer usingcoordinating reducing reagents, such as borohydrides or aluminiumhydrides (see, U.S. Pat. Nos. 5,684,176 and 5,847,144, both of whichissued to Hilpert).

[0039] In contrast to the teachings of both the scientific and patentliterature, it has now been discovered that the reduction of HMKproceeds with high R,S diastereoselectivity when lithium aluminumt-butoxyhydride (LATBH) is used as the reducing agent. Quitesurprisingly and in contrast to the findings of the prior art, it hasbeen found that the reduction of HMK with LATBH in, for example,diethylether provides a 8:1 mixture of R,S-HMA:S,S-HMA in 97% yield.This high diastereofacial selectivity of the LATBH reducing agent isunusual since reduction of HMK with similar reducing agents, such aslithium aluminum hydride or sodium borohydride, do not favor R,Sdiastereoselectivity (see, U.S. Pat. Nos. 5,684,176 and 5,847,144, bothof which issued to Hilpert). TABLE I HMK Reductions: Reagent(s)Solvent(s) Temp Time R,S:S,S Li(OtBu)3AIH Et2O  0 C.  3 Hrs 8:1 (+)-DipChloride ™ (1.4eq) THF 5C-RT 12 Hrs 5:1 K-Selectride ® THF Reflux  2 Hrs2:1 K-Selectride ®/Ti(OiPr)4 THF 25 C. 30 Min 2:1 KS-Selectride ® THF RT 2 Hrs 2:1 K-Select./MgBr2*OEt2 THF RT 30 Min 2.6:1 R-AlpineBorane(Conc.) THF Reflux  9 Dys 1:1 L-Selectride ® THF R.T.  1 Hr 0.9:1NaBH4/CeCl3(anh.) THF RT  2 Hrs 0.8:1 N-Selectride ® EtOH/THF R.T.  2Hrs 0.7:1 NaBH4/CeCl3*7H2O THF 25 C. 18 Hrs 0.7:1 NaBH4/EDTA(Na2*2H2O)THF RT 30 Min 0.7:1 NaCNBH3 THF RT 36 Hrs 0.7:1 (+)-2-Butanol/NaBH4 THFRT  1 Hr 0.6:1 Cp2TiBH4 Glyme R.T. 30 Min 0.6:1 NaBH4 THF 25 C.  2 Hrs0.6:1 NaBH4/(−)-2-Butanol THF RT 30 Min 0.6:1 NaBH4/Al(OiPr)4 THF Reflux 2 Hrs 0.6:1 NaBH4/DiacetoneDglucose THF RT 12 Hrs 0.6:1 NaBH4/EDTA THFRT 12 Hrs 0.6:1 NaBH4/L-Tartaric Acid THF 5 C.  1 Hr 0.6:1NaBH4/MgBr2*OEt2 THF RT  1 Hr 0.6:1 BH3-t-butylamine THF R.T.  1 Hr0.5:1 LAH THF 25 C.  1 Hr 0.5:1 LS-Selectride ® THF RT  1 Hr 0.5:1NaBH4/D-Tartaric Acid THF RT 30 Min 0.5:1 (+)-2-Butanol * BH3 THF RT  1Hr 0.4:1 NaBH4/CaCl2 MeOH R.T.  1 Hr 0.4:1 AminoAlcohol Borane THF 25 C.12 Hrs 0.3:1 Na(PEG)2BH2 THF RT 30 Min 0.3:1 THF*BH3 EtOH/THF R.T.  2Hrs 0.2:1 Al(iOPr)3 IPA 50 C.  3 Dys 0.05:1 Na HB(OCH3)3 MeOH RT  1 Hr1:1

[0040] As such, in one embodiment, the present invention provides amethod for preparing an R,S-halomethyl alcohol (R,S-HMA) compound havingthe following general formula:

[0041] the method comprising: reducing a compound having the followinggeneral formula:

[0042] with a non-chelating, bulky reducing agent to form the R,S-HMAcompound.

[0043] In the above formulae, R¹ is an amino acid side chain. Moreparticularly, in the above formulae, R¹ is a side chain from any of thenaturally occurring amino acids or amino acid mimetics. In a preferredembodiment, R¹ is a benzyl group, a substituted benzyl group, anS-phenyl group, an alkyl group or a para-nitrobenzene group. In an evenmore preferred embodiment, R¹ is a benzyl group. R², in the aboveformulae, is a blocking or protecting group. It will be readily apparentto those of skill in the art that suitable-amino blocking groupsinclude, for example, those known to be useful in the art of stepwisesynthesis of peptides. Included are acyl type protecting groups (e.g.,formyl, trifluoroacetyl, acetyl, etc.), aromatic urethane typeprotecting groups (e.g., benzyloxycarboyl (Cbz), substituted Cbz, etc.),aliphatic urethane type protecting groups (e.g., t-butyloxycarbonyl(Boc), isopropylcarbonyl, cyclohexyloxycarbonyl, etc.) and alkyl typeprotecting groups (e.g., benzyl, triphenylmethyl, etc.). In a presentlypreferred embodiment, the blocking group is selected from the groupconsisting of Boc, Cbz and Moc. In the above formulae, X¹ is a leavinggroup. Suitable leaving groups will be readily apparent to those ofskill in the art. In a presently preferred embodiment, the leaving groupis a halo group (e.g., Cl, Br, F or I). In an even more preferredembodiment, X¹ is a chloro or bromo group. Although many of thecompounds disclosed herein contain the exemplar designation “halo,” suchas halomethyl ketone (HMK) or halomethyl alcohol (HMA), it will bereadily apparent to those of skill in the art that other leaving groupscan be used in place of the halo group.

[0044] In the above embodiment, the reduction is carried out using anon-chelating, bulky reducing agent. It has surprisingly been discoveredthat non-chelating, bulky reducing agents favor the S,R-diastereomer.Examples of non-chelating, bulky reducing agents suitable for use in themethods of the present invention include, but are not limited to,lithium aluminum t-butoxyhydride (LATBH), sodiumtris-t-butoxyborohydride (STBH). In a presently preferred embodiment,the non-chelating, bulky reducing agent is LATBH. Once formed, theR,S-HMA can be reacted with an alkali metal base to form an R,S-epoxide.An exemplar embodiment of the above method is illustrated by thefollowing reaction scheme:

[0045] Synthesis of R,S-Boc-Epoxide by LATBH Reduction

[0046] In this embodiment, the reduction is preferably carried out in asolvent. It will be readily apparent to those of skill in the art thatnumerous solvents can be used. Exemplar solvents include, but are notlimited, to the following: diethyl ether, THF, MTBE and mixturesthereof. Quite surprisingly, it has been found that the reduction ofLATBH is dependent on the solvent employed. For instance, when diethylether is used as the solvent, a 8:1 mixture of R,S-HMA:S,S-HMA isobtained. However, when THF or MTBE is used as the solvent the ratio ofR,S-HMA:S,S-HMA is less than or equal to about 2:1. Based on theseresult, it is thought that a variety of factors, such as steric,solvation and chelation, are responsible for the high R,Sdiastereoselectivity observed in LATBH reduction of HMK. Thus, whenLATBH is used as the reducing agent, diethyl ether is preferably used asthe solvent.

[0047] LATBH is commercially available as a white powder and is used asa suspension in diethyl ether. Alternately, LATBH can be prepared insitu by the reaction of LAH with 3 equivalents of t-butylalcohol indiethylether and then reacted with HMK. The best solvent, as judged onbasis of R,S-diastereoselectivity, is diethyl ether. However, thesolubility of HMK in diethyl ether is relatively low and a large amountof diethyl ether is needed to dissolve CMK, thereby reducing reactorefficiency to some extent. The reactor efficiency can be improved byeither adding HMK as a solid or, alternatively, as a solution in asecondary solvent (e.g., THF, toluene, ethyl acetate, etc.) to asuspension of LATBH in diethyl ether. The reaction rate is not affected,but the diastereoselectivity can be reduced from 8:1 in pure diethylether to about 5:1 with the above modifications.

[0048] In this embodiment, the reduction can be carried out at atemperature ranging from about −30° C. to about 25° C. In a presentlypreferred embodiment, the reduction is carried out at a temperatureranging from about −5° C. to about 5° C. At lower temperatures, largeramounts of solvent are needed to maintain homogeneity; whereas at hightemperatures, formation of the epoxide, resulting from intramolecularcyclization, is observed. At 0° C., the reduction reaction is rapid andis complete in less than about 30 minutes. It will be readily apparentto those of skill in the art that the progress of the reduction reactioncan be monitored by, for example, HPLC, and the reaction is deemedcomplete when the amount of unreacted HMK is less than about 1%.

[0049] In another embodiment, the present invention provides a methodfor preparing an R,S-halomethyl alcohol (R,S-HMA) compound having thefollowing general formula:

[0050] the method comprising: reducing a halomethyl ketone (HMK)compound having the following general formula:

[0051] with a reducing agent selected from the group consisting ofsodium cyanoborohydride, cerium chloride/sodium borohydride,K-Selectride®, KS-Selectride® and (+)-Dip Chloride™ to form the R,S-HMAcompound. In this method, R¹ is an amino acid side chain; R² is ablocking group; and X¹ is a leaving group. It will be readily apparentto those of skill in the are fully applicable to this method and, thus,will not be repeated.

[0052] As with the previously described method, the reduction ispreferably carried out in a solvent. It will be readily apparent tothose of skill in the art that numerous solvents can be used. Exemplarsolvents include, but are not limited, to the following: diethyl ether,THF, MTBE and mixtures thereof. In a preferred embodiment, diethyl etheror THF is employed as the solvent. Moreover, as with the previouslydescribed method, the reduction can be carried out at a temperatureranging from about −30° C. to about 25° C. In a presently preferredembodiment, the reduction is carried out at a temperature ranging fromabout −5° C. to about 5° C.

[0053] In yet another embodiment, the present invention provides amethod for isolating an R,S-halomethyl alcohol (R,S-HMA) from a mixtureof R,S-HMA and S,S-HMA. S,S-HMA is crystalline and is relatively easy topurify. In contrast, the R,S-HMA is soluble in most organic solvents andis difficult to purify by standard purification techniques, such asrecrystallization. Mixtures of R,S-HMA and S,S-HMA can be separated bycolumn chromatography or by preparative scale HPLC, but are notpractical economically.

[0054] It has now been discovered that a mixture of R,S-HMA and S,S-HMAcan be separated on the basis of differential solubility; R,S-HMA issoluble in hot hexanes, whereas the crystalline diastereomer, S,S-HMA,is not. As such, the present invention provides a method for isolatingan R,S-halomethyl alcohol (R,S-HMA) from a mixture of R,S-HMA andS,S-HMA, the method comprising: combining the mixture of R,S- andS,S-HMAs with hexane and heating to a temperature ranging from 50° C. toabout 60° C. to produce a hexane extractant; cooling the hexaneextractant to a temperature ranging from about 0° C. to about 10° C.,filtering the hexane extractant to form a first retentate and recoveringthe first retentate; combining the first retentate with hexane to form ahexane solution, heating the hexane solution to a temperature rangingfrom about 50° C. to about 60° C., and cooling the hexane solution to atemperature ranging from about 30° C. to about 40° C. to produce asuspension; and filtering the suspension to form a second retentate andrecovering the second retentate, wherein the R,S-HMA is present in thesecond retentate.

[0055] For instance, a crude reaction mixture, consisting of 50-90%R,S-HMA, 10-50% S,S-HMA and 0-10% Me-ester, was extracted with hothexane and the resulting hexane extractant was cooled to 10° C. andfiltered to provide about 94% pure R,S-HMA in 74% yield (based on HMK);the major contaminant was S,S-HMA (5%). Attempts to purify the 94% purematerial by differential solubility (above treatment) or byrecrystallization from a variety of solvent/solvent mixtures were notcompletely successful. However, it has been determined that the best wayto purify the 94% pure R,S-HMA is to dissolve it in hot hexane (about60° C.), cool to about 40° C., and then allowing the mixture tocrystallize at about 35° C. to about 37° C. for at least 2 h. Thecrystallized product is then filtered at about 30° C. to about 35° C. toprovide about 99.5% pure R,S-HMA in 83% recovery. Interestingly, it hasbeen found that if the mixture is cooled to 25° C. and filtered, amixture consisting of about 94.5% R,S-HMA and 5.5% S,S-HMA, is obtained.This result is surprising because S,S-HMA is should be the first tocrystallize. Although a variety of solvent/solvent mixtures, such asmethanol, methanol/water, toluene, dibutyl ether, etc., have been usedto purify 94% pure R,S-HMA, the highest degree of purity/recovery isobtained with the hot hexane method of the present invention.

[0056] Once prepared and purified, the R,S-HMA can be converted into anR,S-epoxide. As such, in another embodiment, the present inventionprovides a A method for preparing an R,S-epoxide compound having thefollowing general formula:

[0057] the method comprising: reducing a haloketone (HMK) compoundhaving the following general formula:

[0058] with a non-coordinating reducing agent to form an R,S-haloalcohol(R,S-HMA) compound having the following general formula:

[0059] and contacting the R,S-HMA compof Formula II with an alkali metalbase to form the R,S-epoxide compound. It will be readily apparent tothose of skill in the art that the foregoing discussions relating to R¹,R² and X¹ and their preferred embodiments are fully applicable to thismethod and, thus, will not be repeated. In a presently preferredembodiment, the non-coordination reducing agent is LATBH and thereduction is carried out in diethyl ether. In another presentlypreferred embodiment, the alkali metal base is selected from the groupconsisting of NaOH, KOH, LiOH, NaOCH₃, NaOCH₂CH₃ and KOtBu. In a furtherpreferred embodiment, KOH is the alkali metal base used. In anotherembodiment, calcium hydroxide can be used.

[0060] B. The Inversion Method

[0061] In one embodiment of the inversion method, R,S-epoxide isprepared by a four step process illustrated below. More particularly, inone embodiment of the inversion method, the present invention provides amethod for preparing an R,S-epoxide having the following generalformula:

[0062] the method comprising: (a) reducing a haloketone (HMK) compoundhaving the following general formula:

[0063] with a reducing agent to form an S,S-haloalcohol (S,S-HMA)compound having the following general formula:

[0064] (b) contacting the S,S-HMA compound of Formula II with a memberselected from the group consisting of arylsulfonyl halides andalkylsulfonyl halides in the presence of an amine to form anS,S-halomethyl sulfonyl (S,S-HMS) compound having the following generalformula:

[0065] (c) contacting the S,S-HMS compound of Formula III with anacetate in the presence of a phase transfer catalyst and water to forman R,S-halomethyl acetate (R,S-HMAc) compound having the followinggeneral formula:

[0066] and (d) contacting the R,S-HMAc compound of Formula IV with analkali metal base to form the R,S-epoxide. It will be readily apparentto those of skill in the art that the foregoing discussions relating toR¹, R² and X¹ and their preferred embodiments are fully applicable tothis method and, thus, will not be repeated. In the above formulae, R³is a functional group including, but not limited to, arylsulfonyls andalkylsulfonyls. In a presently preferred embodiment, R³ is a memberselected from the group consisting of a methylsulfonyl group (i.e., amesyl group), a toluenesulfonyl group (i.e., a tosyl group), atrifluoromethanesulfonyl group (i.e., a triflate group) and apara-nitrobenzene sulfonyl group (i.e., a nosyl group). It will bereadily apparent to those of skill in the art that other leaving groupscan be used as R³ in place of the arylsulfonyl and alkylsulfonyl groups.R⁴, in the above formulae, is an acyl group derived from the acetate. Ina presently preferred embodiment, R⁴ is an acetyl group.

[0067] In the first step, i.e., step (a), a HMK is reduced with areducing agent to form an S,S-HMA. In a preferred embodiment, thereducing agent is selected from the group consisting of sodiumborohydride, lithium aluminum hydride and sodium cyanoborohydride. Inanother preferred embodiment, step (a) is carried out in a solvent.Suitable solvents include, but are not limited to, ethanol, methanol,isopropanol, THF, diethyl ether, etc. The reduction can be carried outat a temperature ranging from about −30° C. to about room temperatureand, more preferably, at about −20° C. In a presently preferredembodiment, the reduction step is carried out using sodium borohydridein ethanol to provide a 6:1 mixture of S,S-HMA:R,S-HMA in 98% yield. TheS,S-isomer is highly crystalline and can be easily purified byrecrystallization to provide >99.8% pure S,S-HMA in 80% yield.

[0068] In addition to the foregoing, HMA can also be prepared by MerwinPondroff Verley reduction of HMK. In this process, HMK is reacted withaluminum isopropoxide in refluxing IPA to give S,S-CMA in highdiastereoselectivity. Presumably, under these conditions, the reductionoccurs under chelation control and a mixture of S,S-HMA:R,S-HMA withratios as high as 20:1 is obtained (see, U.S. Pat. Nos. 5,684,176 and5,847,144, both of which issued to Hilpert).

[0069] In the second step, i.e., step (b), an S,S-HMA is reacted with anarylsulfonyl halide or an alkylsulfonyl halide in the presence of anamine to form an S,S-halomethyl sulfonyl (S,S-HMS). Suitable aminesinclude, but are not limited to, trialkylamines (e.g., trimethylamine,triethylamine, etc.), pyridine, 4-dimethylamino pyridine, etc. In apresently preferred embodiment, the amine is triethylamine. Step (b) canbe carried out in a variety of different solvents. Exemplar solventsinclude, but are not limited to, the following: chlorinated solvents(e.g., methylene chloride, dichloroethane, chlorotoluene, etc.),aromatic hydrocarbons (e.g., toluene, xylenes, etc.), ethyl acetate,ethers (e.g., THF, diethyl ether, etc.), etc. In another presentlypreferred embodiment, step (b) is carried out at a temperature rangingfrom about −30° C. to about 100° C. and, more preferably, from about 10°C. to about 70° C.

[0070] In a particularly preferred embodiment of step (b), the S,S-HMAis reacted with methanesulfonyl chloride in toluene in the presence ofan equivalent amount of triethylamine to give the corresponding2S,3S-CMA Mesylate in 98% yield. The reaction is exothermic and is bestconducted at a temperature ranging from about from about 10° C. to about70° C. The crude mesylate is recrystallized from toluene to providegreater than 95% pure S,S-CMA Mesylate in near quantitative yield.However, in the preferred process, S,S-CMA Mesylate is not isolated andthe solution of crude S,S-CMA mesylate in toluene is used, withoutpurification, in the next step, i.e., step (c). Although this mesylationstep can be conducted in a variety of solvents, toluene is the preferredsolvent because it can be used in the next step, thereby eliminating asolvent exchange step from the process.

[0071] In the third step, i.e., step (c), the S,S-HMS is reacted with anacetate in the presence of a phase transfer catalyst and water to from aHMAc. Suitable acetates for use in the present method include, but arenot limited to, the following: cesium acetate, potassium acetate,tetrabutylammonium acetate and sodium acetate. In a presently preferredembodiment, the acetate is cesium acetate. A variety of phase transfercatalysts (PTCs) can be used in carrying out step (c). Exemplar phasetransfer catalysts include, but are not limited to, crown ethers (e.g.,18-crown-6, dibenzo crown ether, etc.), quaternary ammonium salts andquaternary phosphonium salts (e.g., TATB, aliq. 336, etc.). In apresently preferred embodiment, the phase transfer catalyst is a crownether. The crown ether 18-crown-6 is particularly preferred because itallows for the production of R,S-HMAc with least amount of side product.Moreover, the rate of reaction with 18-crown-6 is much faster than withany of the other phase transfer catalysts. In addition, 18-crown-6 canbe easily removed from the product by a simple water wash.

[0072] Step (c), i.e., the displacement reaction, can be carried out ina variety of different solvents. Suitable solvents include, but are notlimited to, hydrocarbons (e.g., hexane, heptane, etc.), aromatichydrocarbons (e.g., toluene, xylene, benzene, etc.) and chlorinatedsolvents (e.g., CCl₄, dichloroethane, chlorotoluenes, etc.). In apresently preferred embodiment, toluene is used as the solvent becauseit can be used for both steps (b) and (c), and it can be used as acrystallization solvent for the R,S-HMAc. In addition, toluene iscommercially available from a variety of sources and can be recycled inhigh efficiency. The displacement reaction, i.e., step (c) can becarried out at a temperature ranging from about 20° C. to about 100° C.In a presently preferred embodiment, the displacement reaction iscarried out at a temperature ranging from about 20° C. to about 100° C.

[0073] In addition to the foregoing, it has been found that thedisplacement reaction is dependent on the amount of water present in thereaction mixture. Presumably, a small amount of water is needed toovercome the lattice energy of the metal acetate, thereby making thenucleophile accessible for the displacement reaction. However, it hasbeen found that increased amounts of water will reduce the reactivity ofthe nucleophile by solvating it. Thus, in a preferred embodiment, thewater is maintained between about 0.5% and about 10.0% and, morepreferably, between about 0.5% and about 5%. Once the displacementreaction is completed, the crude product can be isolated bycrystallization from, for example, toluene/heptane to give typicallygreater than 99.5% pure R,S-HMAc in high yield. Alternately, theR,S-HMAc can be isolated and then recrystallized from, for example,methanol/water to give pure R,S-HMAc.

[0074] In the final step of the above method, i.e., step (d), theR,S-HMAc is reacted with an alkali metal base to form the R,S-epoxide.It has been found that hydrolysis of the R,S-HMAc followed by subsequentintramolecular ring closure provides the R,S-epoxide in nearquantitative yield. In a presently preferred embodiment, the alkalimetal base is selected from the group consisting of NaOH, KOH, LiOH,NaOCH₃, NaOCH₂CH₃ and KOtBu. In another preferred embodiment, step (d)is carried out is a solvent. Suitable solvents include, but are notlimited to, hydrocarbons, aromatic hydrocarbons, chlorinated solventsand ethers (e.g., THF). In a presently preferred embodiment, the solventis a mixture of toluene and THF.

[0075] In a particularly preferred embodiment of step (d), the R,S-HMAcis reacted with aqueous potassium hydroxide (KOH) in a mixture of THFand ethanol. Evaporation of solvent followed by tituration of the crudeproduct with hexane afforded the desired R,S-epoxide as a low melting,white solid.

[0076] Since the R,S-epoxide is soluble in most solvents, it isdifficult to purify. In addition, the R,S-epoxide is reactive towardsring opening reactions and will react with potassium hydroxide inethanol to give the corresponding glycol or the ethoxyglcyol sideproducts. Using this method of the present invention, high purityR,S-epoxide (>>99.5%) has been prepared by incorporating the purity atthe R,S-HMAc stage and then maintaining the purity by minimizing sidereactions in the final step. Thus, it is important that the aboveconversion is achieved in near quantitative yield and without formationof side products. Again, in a preferred embodiment of this method, thisis accomplished by employing aqueous KOH. Presumably, in this form, thehydroxide is nucleophilic enough to allow hydrolysis to occur, but isnot nucleophilic enough to react with the R,S-epoxide and form sideproducts.

[0077] Using this method of the present invention, greater than 99.5%pure R,S-epoxide can be prepared in 95-97% yields. The R,S-epoxideprepared by this process can be characterized by NMR, HPLC, TLC and DSC.Moreover, despite difficulties encountered in the prior art relating tothe purification of the R,S-epoxide, it has now been discovered that theR,S-epoxide can be purified by recrystallization from petroleum ether.This is an important discovery because traditional purificationtechniques, such as chromatography, are not applicable due toinstability of the R,S-epoxide towards silica gel and alumina. As such,in a preferred embodiment, the above method further comprises: purifyingthe R,S-epoxide by recrystallization with petroleum ether. An exemplarembodiment of the above method is illustrated by the following reactionscheme:

[0078] Preparation of the R,S-Epoxide Using One Embodiment of theInversion Method

[0079] In another embodiment of the inversion method, the presentinvention provides a method for preparing an R,S-epoxide compound havingthe following general formula:

[0080] the method comprising: (a) contacting an S,S-halomethyl sulfonyl(S,S-HMS) compound having the following general formula:

[0081] with a carbanate forming acetate to form a cyclic carbamatehaving the following general formula:

[0082] and (b) contacting the cyclic carbamate with an alkali metal baseto form the R,S-epoxide. It will be readily apparent to those of skillin the art that the foregoing discussions relating to R¹, R², R³ and X¹and their preferred embodiments are fully applicable to this method and,thus, will not be repeated. A “carbamate-forming acetate,” as usedherein, refers to an acetate that contains a sufficient leaving group.Exemplar carbamate-forming acetates include, but are not limited to,sodium trichloroacetate, potassium trichloroacetate, tetrabutylammoniumtrichloroacetate, sodium tribromoacetate, potassium tribromoacetatesodium trifluoroacetate and potassium trifluoroacetate.

[0083] As with the previously described methods, step (a) can be carriedout in a variety of solvents, such as hydrocarbons (e.g., hexane,heptane, etc.), aromatic hydrocarbons (e.g., toluene, xylene, benzene,etc.) and chlorinated solvents (e.g., CCl₄, dichloroethane,chlorotoluenes, etc.). In a preferred embodiment, the solvent istoluene. In step (b) of the above method, the cyclic carbamate isreacted with an alkali metal base to form the R,S-epoxide. In apresently preferred embodiment, the alkali metal base is selected fromthe group consisting of NaOH, KOH, LiOH, NaOCH₃, NaOCH₂CH₃ and KOtBu. Inanother preferred embodiment, step (b) is carried out in a solvent.Suitable solvents include, but are not limited to, hydrocarbons,aromatic hydrocarbons, chlorinated solvents and ethers (e.g., THF). In apresently preferred embodiment, the solvent is a mixture of THF andethanol.

[0084] In connection with the above method, the present inventionprovides a cyclic carbamate compound having the following generalformula:

[0085] In the above formula, R¹ is an amino acid side chain (e.g.,benzyl); R² is hydrogen or a blocking/protecting group (e.g., BOC, MOC,CBZ, etc.); and X¹ is a leaving group (e.g., a chloro or bromo group).This compound can be readily synthesized and purified using the methodsset forth in Example II.

[0086] C. The Alkene Method

[0087] In another embodiment, the present invention provides a methodfor preparing an alkene having the following general formula:

[0088] the method comprising: (a) contacting a compound having thefollowing general formula:

[0089] with a hydrohalo acid to form a compound having the followinggeneral formula:

[0090] (b) reducing a compound of Formula II with a reducing agent toform a compound having the following general formula:

[0091] and (c) dehalohydroxylating a compound of Formula III to form thealkene. It will be readily apparent to those of skill in the art thatthe foregoing discussions relating to R¹, R², and X¹ and their preferredembodiments are fully applicable to this method and, thus, will not berepeated.

[0092] In step (a), a compound of Formula I is reacted with a hydrohaloacid to form a compound of Formula II. Suitable hydrohalo acids include,but are not limited to, hydrobromic acid, hydrochloric acid andhydroiodic acid. In a presently preferred embodiment, the hydrohalo acidis hydrobromic acid or hydrochloric acid. Step (b) can be carried outusing any of a variety of reducing agents. In a presently preferredembodiment, sodium borohydride is the reducing agent employed in step(b). Finally, in step (c), compound III is dehalohydroxylated to formthe desired alkene. Suitable dehalohydroxylating compounds include, butare not limited to, zinc (0) metals (e.g., zinc dust), nickel metals,zinc mercury amalgan, etc. Step (c) can be carried out in a number ofdifferent solvents. Suitable solvents include, but are not limited to,methanol, ethanol, isopropanol, THE, MTBE, toluene, etc. In a presentlypreferred embodiment, zinc dust in ethanol is used in step (c).

[0093] Once prepared, the alkene can be converted to the R,S-epoxideusing, for example, m-chloroperbenzoic acid as illustrated below.

[0094] In one particularly preferred embodiment of this method, reactionof the diazoketone (i.e. the compound of Formula I), which is preparedfrom phenylalanine using diazomethane, with hydrobromic acid gives thebromoketone (i.e., the compound of Formula II) in 77% yield. Reductionof the bromoketone with sodium borohydride under conditions similar tothose used for the chloroketone gave high selectivity for theS,S-bromomethylalcohol (i.e., the compound of Formula III) over theR,S-diastereomer. The desired S,S-isomer was isolated in 85% yield afterrecrystallization (see, Parkes, et al., J. Org. Chem. 1994 39, 3656).

[0095] The bromomethylalcohol was dehalohydroxylated to give the olefin(i.e., the compound of Formula V) by zinc metal in ethanol. Upon workup, the t-BOC protected S-3-amino-4-phenyl-1-butene was isolated in 77%yield. Using this method of the present invention, very pure materialwas prepared without the problems of racemization associated with thereaction of the t-BOC protected S-phenylalanal route. the alkene wasconverted to the R,S-epoxide using, for example, a published route usingm-chloroperbenzoic acid. An exemplar embodiment of the above method isillustrated by the following reaction scheme:

[0096] Preparation of the R,S-Expoxide Using the Alkene Method

[0097] The invention will be described in greater detail by way ofspecific examples. The following examples are offered for illustrativepurposes, and are not intended to limit the invention in any manner.Those of skill in the art will readily recognize a variety ofnoncritical parameters that can be changed or modified to yieldessentially the same results.

EXAMPLES A. Example I

[0098] This example illustrates the preparation of S,S-CMA and R,S-CMAusing the reduction methods of the present invention.

[0099] 1. Preparation of S,S-CMA by Reduction

[0100] A 500 mL, 3-necked round bottom flask was fitted with acondenser, thermocouple temperature probe, dry nitrogen inlet, andmagnetic stirring. A stirred solution of chloromethylketone (CMK) (19.22g, 0.0645 mol) and Isopropanol (200 mL) was heated to 50° C. andaluminum isopropoxide (6.87 g, 0.0337 mol, 1.5 eq) was charged to thereactor. The reaction mixture was heated at 50° C. for three hours atwhich point HPLC analysis indicated 0.4% CMK remained. After heating for1 additional hour and cooling to room temperature, the reaction wasquenched with water (200 mL) and glacial acetic acid (˜50 mL) to adjustthe pH to 4. The reaction was transferred to a separatory funnel and theorganic solids were extracted into ethyl acetate, resulting in two clearphases. The phases were split and the organic phase was evaporated to18.63 g (97% yield) off-white solid. S,S-Chloromethylalcohol (S,S-CMA):¹H NMR (CDCl₃): δ1.37 (s, 9 H), 2.97 (m, 2 H, J=5.1 Hz), 3.20 (br d, 1H), 3.55-3.69 (m, 2 H), 3.83-3.93 (m, 2 H), 4.59 (br d, 1 H, J=6.6 Hz),7.21-7.34 (m, 5 H); HPLC (Short) t_(R) 3.84 min=99.51%, 4.66 min=0.49%;HPLC (long) t_(R) 13.26 min=99.50%, 17.42 min=0.50%.

[0101] Proton NMR analysis of final product indicated ˜37:1 ratio ofS,S:R,S Boc-phenylalanine Chloromethylalcohol (CMA), and traces ofacetic acid. HPLC analysis indicated ˜32:1 ratio of S,S:R,S CMA (95.1%S,S CMA, 3.0% R,S CMA, 0.6% CMK, and 1.3% impurities from the startingmaterial e.g. methyl ester, boc-phenylalanine). Further purification wasaccomplished by recrystallization from heptane.

[0102] 2. Sodium Cyanoborohydride Reduction of CMK

[0103] To a solution of sodium cyanaoborohydride (5.28 g, 84.0 mmol, 1.0eq) in THF (25 mL) was added a solution of CMK (25.0 g, 84.0 mmol) inTHF (100 mL), followed by addition of AcOH (10 mL) over 0.5 h at RT.During this addition, internal temperature was never allowed to riseabove 42° C. After 1.5 h, TLC analysis of an aliquot indicated totalconsumption of CMK signaling reaction completion. The reaction mixturewas quenched with H₂O (250 mL) and the resulting white slurry wasstirred at ambient temperature for 1 h. The mixture was extracted withethyl acetate (500 mL) and then concentrated on a rotary evaporator to avolume of ca. 300 mL. Water (100 mL) and the remaining ethyl acetate wasremoved under reduced pressure at 45° C. The precipitated product wasfiltered, washed with water (200 mL), and dried in a vacuum oven at 45°C./28 inch-Hg for 15 h to give 23.8 g (95% yield) of a white solid. HPLCanalysis revealed that the solid contained a mixture of 41% R,S-CMA and59% S,S-CMA.

[0104] 3. Preparation of R,S-CMA by Reduction with CeriumChloride/Sodium Borohydride.

[0105] A 5000 mL, 3-necked round bottom flask was fitted with mechanicalstirring, Claisen head adapter, condenser, dry nitrogen inlet, glassenclosed thermocouple temperature probe, and solids addition funnel, alloven dried at 120° C. and cooled under dry nitrogen. To a stirred slurryof CMK (200 g, 0.672 mol, 1.0 eq), cerium chloride heptahydrate (250 g,0.672 mol, 1.0 eq), and THF (716 g) was added sodium borohydride (25.5g, 0.673 mol, 1.0 eq) portionwise over 70 minutes during which time a4.5° C. exotherm was observed. The reaction mixture was stirred for anadditional 5 hours at room temperature, at which time HPLC analysisindicated that starting material had been consumed. The reaction wascooled to 2° C. and ethyl acetate (500 mL) was added. The reaction wasquenched with water (1000 mL) at a rate to control the production ofhydrogen gas and maintain at a temperature of less than 20° C. The pH ofthe reaction was adjusted to approximately 6 with glacial acetic acid(18 mL) and additional ethyl acetate (2500 mL) was added to dissolve thesolids. The reaction was warmed to room temperature and transferred to a6000 mL separatory funnel. The organic phase was separated, washed withwater and evaporated in vacuo to give 175 g (96% yield) of a whitesolid. HPLC analysis of the solid indicated 36% R,S boc-phenylalaninechloromethylalcohol (CMA) and 60% S,S CMA; ¹H NMR analysis confirmed a0.6:1 R,S:S,S CMA ratio.

[0106] 4. Preparation of R,S-CMA by Reduction with LATBH.

[0107] Lithium tri-t-butoxyaluminohydride (LATBH) (93.87 g, 0.369 mol,1.1 eq) and anhydrous diethyl ether (500 mL) were placed in a reactorand cooled to 2° C. A solution of CMK (99.84 g, 0.355 mol) and anhydrousdiethyl ether (2000 mL) was added over 90 min maintaining an internaltemperature of less than 5° C. After the addition was complete, themixture was stirred for 30 min at which point HPLC analysis indicated nostarting material remaining. The reaction was slowly quenched water(1500 mL) and then acetified with glacial acetic acid (1000 mL) at arate such the temperature was below 10° C. The reaction was warmed toambient and the organic phase was separated, washed with water and wasevaporated in vacuo to give an orange oil (100.12 g). Hexanes (500 mL)was added to the flask and evaporated on the rotary evaporator to removeresidual t-butanol and isobutanol; the evaporation yielded an orangeoil/solid (97.34 g, 97% yield).

[0108] HPLC and ¹H NMR analysis indicated an approximately 6.5:1 ratioof R,S:S,S CMA. The R,S-isomers was purified by extraction intorefluxing hexanes (300 mL), filtration while hot to remove the lesssoluble S,S-isomer, and slow cooling overnight. After filtration anddrying, 74.5 g (82.3% yield) of a product that was 92.1% R,S CMA and5.4% S,S CMA by HPLC and ¹H NMR analysis.

[0109] 5. Purification of Mixtures of S,S- and R,S-CMA

[0110] CMA (170 g of a mixure of 0.6 to 1 isomers) and hexanes (800 g)were charged to the flask and heated to reflux for 1 hour. The lesssoluble isomer mix (90% S,S CMA, 9% R,S CMA) (99.6 g, 58% yield) wasremoved by filtration of the hot mixture. The filtrate was evaporated to75% volume, cooled and filtered to give the more soluble isomer mix (94%R,S CMA, 3% S,S CMA) 36.7 g (22% yield) were removed by cold filtrationthrough a 600 mL coarse, sintered glass funnel. The residual filtratewas dryed in vacuo to give a yellow oil (18.6 g, 11% yield) containing amixture of isomers.

[0111] A mixture of 32 g of the crude solid (93% R,S-CMA and 6% S,S-CMA)from the hot hexane recrystallization and hexanes (600 mL) was heated to60° C. The resulting solution was slowly allowed to cool to 53° C. andseeded with R,S-CMA crystals. Further crystallization was observed at37° C. at which point significant amount of white needles had formed insolution. The internal temperature was maintained between 35-40° C. for1.5 h, at which point the mixture was hot filtered to provide 25.7 g(80% recovery) of R,S-CMA as white needles. HPLC analyses revealed thatR,S-CMA was 99.8% pure and contained ca. 0.2% S,S-CMA. Concentration ofhexane filtrate on a rotary evaporator afforded 6.1 g of a white solidwhich based on HPLC analysis was found to be consist of 91.9% R,S-CMAand 6.4% S,S-CMA.

[0112] R,S-Chloromethylalcohol (R.S-CMA): ¹H NMR (CDCl₃): δ1.36 (s, 9H), 2.94 (m, 2H, J=7.3 Hz), 3.54 (d, 2 H, J=4.6 Hz), 3.77 (m, 1 H, J=2.1Hz), 3.94 (m, 1 H, J=7.3 Hz), 4.99 (d, 1 H, J=8.8 Hz), 7.24 (br m, 5 H);HPLC (Short) t_(R) 3.87 min=0.21%, 4.69 min=99.79%.

B. Example II

[0113] This example illustrates the preparation of R,S,-Epoxide usingtwo different inversion methods. In NMR: Varian 300 MHz; HPLC: HewlettPackard 1100, column C18 reverse phase using acetonitrile/water withphosphate buffer; melting points were measured by DSC

[0114] 1. Preparation of R,S-Epoxide by the Inversion Route Via AnAcetate

[0115] a. Step 1: Mesylation

[0116] A 3 L jacketed reactor equipped with a mechanical stirrer,addition funnel, reflux condenser, temperature probe, and a nitrogen gasinlet was charged with S,S-CMA (150.3 g, 0.501 mol) and toluene (1.5 L).The system was flushed with nitrogen and triethylamine (62 g, 0.613 mol)was added. The resulting mixture was treated, dropwise, withmethanesulfonyl chloride (69 g, 0.595 mol). The rate of addition ofmethanesulfonyl chloride was maintained so as to control the reactiontemperature below 50° C. When the addition was complete, the reactionmixture was stirred for 1 h, sampled and analyzed by HPLC whichindicated that the reaction was complete. The reaction mixture wasslowly quenched into 10% aqueous potassium bicarbonate solution, and theorganic phase was separated and washed with water. The organic layercontaining the mesylate derivative was then dried azeotropically andused without isolation in the displacement reaction. In order to obtainyield/purity data, a sample of reaction mixture was withdrawn andstripped off solvent under reduced pressure to give S,S-CMA mesylate, apale yellow solid: mp 117-121° C.; ¹H NMR (CDCl₃): δ1.35 (s, 9 H), 2.79(br t, 1 H, J=11.1 Hz), 3.04 (dd, 1 H, J=14.4, 4.8 Hz), 3.17 (s, 3 H),3.73 (m, 2 H, J=4.5 Hz), 4.15 (ddd, 1 H, J=5.1, 4.8, 3.6 Hz), 4.69 (brd, 1 H, J=6.6 Hz), 5.04 (br s, 1 H), 7.20-7.34 (m, 5 H); HPLC revealedthat the product was 99.7% (area %) pure.

[0117] b. Step 2: Displacement

[0118] A second reactor was charged with cesium acetate (241.7 g, 1.125mol) and 18-crown-6 (33 g, 0.125 mol) in toluene (400 mL) and themixture was heated to 70 C. Next, a solution of S,S-CMA mesylate intoluene was added over 1 h and the resulting mixture was heated at 70°C. for an additional 9 hrs at which time TLC analysis indicated thereaction was complete. The reactor was cooled to 35° C., and water (1 L)was added. The organic layer was separated and washed with water and thesolvent was evaporated until the concentration of the product was 20% byweight as determined by 1 H NMR analysis. Heptane (1350 g) was added andthe mixture heated to 55° C. for 30 min, and cooled to ambient over 1 h.The mixture was then cooled to 5° C., filtered, and the white solid wasdried in vacuo to give 131.5 g (77% yield) of(2R,3S)-N-t-butoxycarbonyl-1-chloro-2-acetoxy-4-phenylbutanamine, awhite solid: mp 105-106° C.; ¹H NMR (CDCl₃): δ1.39 (s, 9 H), 2.13 (s, 3H), 2.75 (br d, 2 H, J=7.5 Hz), 3.56 (br d, 2 H, J=6.3 Hz), 4.24 (ddd, 2H, J=7.4, 2.2 Hz), 4.52 and 4.67 (both br d, 1 H total, J=9.6 Hz),5.03-5.12 (m, 1 H, J=6.2, 2.1 Hz), 7.17-7.33 (m, 5 H); TLC (silica gel,30% EtOAc/Hexane): R_(f)=0.75; HPLC analysis revealed that the productwas 99.7% pure.

[0119] c. Step 3: Hydrolysis and Ring Closure

[0120] A 1 L flask fitted with a mechanical stirrer, addition funnel,temperature probe, and a nitrogen inlet was charged with R,S-CMA Acetate(34.3 g, 100.4 mmol), THF (156 mL), ethanol (90 mL) and water (30 mL).The mixture was cooled to 0-3° C. and a 43% aq. KOH solution (13.3 g of86% potassium hydroxide dissolved in 13.3 mL of water) was addeddropwise to the reaction mixture so as to maintain an internaltemperature of <5° C. The reaction mixture was stirred at 0-3° C. for1.5 h and then quenched with 6% aq. sodium biphosphate solution (250mL); the reaction temperature was maintained below 10° C. during quench.Diethyl ether (260 mL) was added and the organic layer was separated,dried (Na₂SO₄), filtered, and stripped of solvent under reduced pressureto give a clear oil. Hexane (130 mL) was added and the resulting mixturewas concentrated on a rotary evaporator till <10% hexane remained andthe residue was seeded with crystals of pure R,S-Epoxide. The mixturewas then stored at room temperature for 16 h and the precipitated solidwas collected by filtration and dried to provide 25.4 g (96%) of thetitle compound, a white solid: mp (DSC): 51.56° C.; ¹H NMR (CDCl₃):δ1.39 (s, 9 H), 2.59 (s, 1 H), 2.70 (dd, 1 H, J=3.9 Hz), 2.91 (m, 2 H,J=6.6 Hz), 3.01 (m, 1 H, J=3.6 Hz), 4.13 (d, 1 H, J=7.8 Hz), 4.49 (d, 1H, J=7.2 Hz), 7.27 (br m, 5 H). The purity, as determined by HPLCanalysis, was 99.5%.

[0121] d. Alternate Process for Preparation of 2R,3S-Chloromethylacetate

[0122] A 4 L jacketed reactor equipped with a mechanical stirrer, refluxcondenser, temperature probe, and a nitrogen gas inlet was charged withS,S-CMA Mesylate (246.5 g, 0.65 mol) and 18-crown-6 (43.4 g, 0.16 mol),cesium acetate (322.8 g, 1.685.7 mol) and toluene (3.2 L). The resultingmixture was heated at 72° C. for 11 hours, at which point TLC analysis(silica gel, 30% EtOAc/Hexane) indicated the starting material had beenconsumed. The organic phase was separated and concentrated under reducedpressure to provide a white solid. The residue was dissolved in ethylacetate (1.2 L) and the resulting solution was washed with H₂O (2×550mL), dried (Na₂SO₄), filtered, and stripped off solvent under reducedpressure to provide 216 g (97%) of 92% pure R,S-CMA Acetate.Recrystallization of the crude product from 85:15 methanol/waterprovided 99.7% pure R,S-CMA Acetate in 57% yield. The mother liquor wasconcentrated on rotary evaporator, treated with water, and chilled to 5°C. to provide an additional 22 g of 98.2% pure product, thus increasingthe total yield of R,S-CMA Acetate to 76%.

[0123] 2. Preparation of R,S-Epoxide by the Inversion Route ViaTrichloroacetic Acid

[0124] a. Step 1: Preparation of ‘Cyclic Carbamate’

[0125] A 250 ml round-bottom flask equipped with a magnetic stir bar,reflux condenser, temperature probe, and a nitrogen gas inlet wascharged with 9.98 g (26.4 mmol) of S,S-CMMs, 0.434 g (1.35 mmol) oftetrabutylammonium bromide (TBAB), 7.46 g (40.2 mmol) of sodiumtrichloroacetate, and flushed vigorously with N₂. Toluene (104 mL, 90 g)was added under a steady stream of N₂ and the resulting slurry washeated to ˜45° C. The reaction mixture was stirred at 45° C. overnight,at which point TLC analysis (silica gel, 30% EtOAc/Hexane) indicated thestarting material had been consumed. The toluene phase was transferredfrom the reaction vessel into a 500 mL separatory funnel and EtOAc/H2O(50 mL/100 mL), used to rinse the reactor, was combined with the organiclayer. After separating the two layers, the organic layer was washedwith H₂O (1×100 mL), dried over Na₂SO₄, filtered, and removed undervacuum. The resulting crude solid was dried in a vacuum oven (45° C.)overnight to provide a yield of 92% (7.92 g, 24.3 mmol, ˜90% pure).

[0126] This product was combined with the crude cyclic carbamate (1.67g, 5.13 mmol) from a previous small scale synthesis (CP078-24) andcrystallized from MeOH/H₂O as follows: 9.59 g of crude product wasdissolved in 43 mL (34 g) of MeOH while heating to 45° C. To this warmMeOH solution was slowly added to 4 mL of H₂O and the temperatureallowed to reach ambient without agitation. Needle formation was rapidand the flask was cooled to 0-5° C. prior to filtration, yielding 7.24 g(75.5% recovery) of product (99.42% pure).

[0127] b. Step 2: Preparation of R,S-Epoxide

[0128] To a 50 mL round-bottom flask equipped with a magnetic stir bar,temperature probe, and a nitrogen inlet was added a 43% aqueous KOHsolution (0.73 g soln., 5.82 mmol) and 1.0 g of H₂O. The contents of theflask were cooled to 0-3° C. with the aid of an ice-bath. A separateflask was charged with 0.99 g (2.22 mmol) of the ‘cyclic carbamate’, 3.2g of THF, and 1.6 g of EtOH and agitated to dissolve all solids. The‘cyclic carbamate’ solution was added dropwise to the reaction flask viapipet so as to maintain an internal temperature of <4° C. Once additionwas complete, the reaction was stirred at 0-3° C. for ˜1 hour, at whichpoint the reaction was quenched by addition of a sodium biphosphatesolution (0.448 g NaH₂PO₄, 6.8 g H₂O). The reaction quench was conductedat such a rate as to keep the internal temperature <10° C. (Note: Thereaction was analyzed for completion via TLC after a 30 min. post-stirand found to contain the desired epoxide.) The cloudy reaction mixturewas diluted with 10 mL of Et₂O and the layers were separated. The clearorganic layer was dried over Na₂SO₄, filtered, and the solvent wasremoved under vacuum to afford a clear oil (0.8 g).

[0129] The crude product was taken up in 20% EtOAc/hexanes (due tosolubility problems in desired eluent) and purified via columnchromatography (silica gel, 10% EtOAc/hexanes). R,S-epoxide, as well asa small amount of a nonpolar impurity, were collected prior to running agradient to 50% EtOAc/hexanes to collect the deblocked impurity. The twofractions were evaporated of solvent to obtain clear oils: R,S-epoxide:0.444 g (solidified under vacuum; HPLC: ˜90%). The identity of theR,S-epoxide was confirmed by ¹H NMR, HPLC, and TLC.

[0130] c. Mechanistic Discussion

[0131] Without intending to be bound by any theory, it is thought thatthe reaction occurs through the following mechanism. Attack of atrichloroacetate anion on the secondary mesylate in an SN₂ fashioninverts the stereochemistry and provides the intermediateR,S-chloromethyltrichloroacetate (R,S-CMAcCl₃). Due to the excellentleaving group ability of:CCl₃ (trichlorocarbene), nucleophilic attack ofthe carbamate nitrogen on the acetate carbonyl and subsequent (orconcurrent) loss of a proton provides the cyclic carbamate. It isthought that treatment of this species with aqueous base favors reactionof the hydroxide at the cyclic carbonyl, possibly due to the addedbenefit of relieving the ring strain of the molecule, resulting in theexpected epoxide (55-60%).

C. Example III

[0132] This example illustrates the preparation of the R,S-epoxide bythe epoxidation of an alkene.

[0133] 1. Preparation of Bromomethyl Ketone (BMK):

[0134] A solution of diazomethyl ketone (DMK) in ethyl acetate/diethylether (16.8 g solution, 1 g DMK, 3.5 mmol) was cooled to 5° C. andtreated dropwise with a solution of hydrobromic acid (1.8 g, 10.6 mmol);the reaction temperature was maintained below 10° C. during theaddition. The resulting mixture is stirred at 0-5° C. for 2 hours andquenched with water (20 mL). The organic layer was separated and washedwith water (3×20 mL) until the pH of the final water wash was >6. Theorganic layer was concentrated on a rotary evaporator to give 0.92 g(77%) of an off-white solid. The product purity, as determined by HPLC,was 91%. ¹H NMR-(S,S-BMK; CDCl₃₎): δ1.41 (s, 9 H), 3.07 (m, 2 H, J=6.6Hz), 3.94 (m, 2 H, J=16.2 Hz), 4.72 (q, 1 H, J=7.2 Hz), 5.07 (d, 1 H,J=7.5 Hz), 7.20-7.31 (br m, 5 H).

[0135] 2. Preparation of Bromomethylalcohol (BMA):

[0136] A mixture of bromomethylketone (20.3 g, 59.3 mmol), ethyl acetate(160 mL), and ethanol (240 mL) was cooled to −30° C. and treated,dropwise, with a slurry of sodium borohydride (1.16 g, 30.7 mmol) inethanol (80 mL). The reaction mixture was stirred at −30° C. for 30 min.and quenched with acetic acid (4 mL); the reaction temperature wasmaintained below −20° C. during the quench. The reaction mixture wasthen warmed to room temperature and treated with water (100 mL) andethyl acetate (150 mL). The layers were separated and the organic layerwas filtered to give 2.8 g of 96.6% pure S,S-BMA. The organic layer wasthen dried (Na₂SO₄), filtered, and evaporated in vacuo to give 14.2 g ofa mixture consisting of 85% S,S-BMA, 6% R,S-BMA, and 5% methyl ester. ¹HNMR (S,S-BMA; CDCl₃): δ1.36 (s, 9 H), 2.98 (br m, 2 H, J=4.5 Hz), 3.46(br m, 1 H, J=9 Hz), 3.54 (br m, 1 H), 3.86 (br s, 2 H), 4.56 (br s, 1H), 7.20-7.31 (m, 5 H); HPLC (Short) t_(R) 2.29 min=0.07%, 3.88min=2.68%, 4.29 min=96.61%, 5.25 min=0.64%.

[0137] 3. Preparation of BOC-Alkene:

[0138] A mixture of crude BMA (12.1 g, 35.2 mmol) prepared above andethanol (240 mL) was heated to reflux and zinc dust (22.4 g, 343 mmole)was added. The resulting mixture was refluxed for 5 h, at which time TLCanalysis (silica gel, 30% EtOAc/Hexane) indicated the starting materialhad been consumed. The reaction mixture was cooled to room temperature,unreacted zinc dust was removed by filtration, and the filtrate wasconcentrated in vacuo to give an oil. This oil was dissolved in ethylacetate (100 mL) and washed with 2% aqueous acetic acid (50 mL). Theorganic layer was separated, dried (Na₂SO₄), filtered and evaporated togive 7.5 g of crude product, an oil; this oil solidified on standing atroom temperature to give a white solid. The solid was dissolved inmethylene chloride (50 mL) and the solution was filtered through 10 g ofsilica gel. Evaporation of the solvent gave 6.0 g (77% yield of thedesired olefin. HPLC analysis showed the olefin was >99% pure.BOC-Alkene: ¹H NMR (CDCl₃): δ1.40 (s, 9 H), 2.83 (br d, 2 H, J=6.6 Hz),4.43 (br s, 2 H), 4.56 (br s, 2 H), 5.06-5.13 (m, 2 H, J=17.4, 10.5, 1.2Hz), 5.8 (ddd, 2 H, J=17.1, 10.5, 5.4 Hz), 7.20-7.31 (m, 5 H); IR (thinfilm): ν3359 (NH), 1686 (CO), 1645 (alkene); HPLC (Short) t_(R) 3.87min=0.65%, 4.01 min=0.04%, 4.69 min=0.19%, 8.38 min=99.12%; MS, m/e MH⁺248.1661.

[0139] 4. R,S-Epoxide by Alkene Route:

[0140] A mixture of BOC-alkene (0.498 g, 2.02 mmol),meta-chloroperbenzoic acid (1.93 g, 8.1 mmol) and dichloromethane (22mL) was stirred at ambient temperature for 3 h at which time HPLCanalysis indicated the starting material had been consumed. The reactionmixture was quenched with aqueous 10% Na₂SO₃ (60 mL), and diluted withdiethyl ether. The organic layer was washed with cold saturated Na₂CO₃(60 mL), brine (60 mL), dried over Na₂SO₄, and the solvent evaporated toprovide a clear oil that solidified on standing. A white solid (0.49 g,1.86 mmol) was isolated in 92% yield and was shown to be a 5.2:1 mixtureof R,S- and S,S-epoxide, respectively (HPLC, 96.5% pure combined).Analysis of the product mixture by proton NMR spectroscopy indicated anapproximate 5.7:1 ratio of diasteriomeric epoxides and no alkenestarting material.

[0141] It is to be understood that the above description is intended tobe illustrative and not restrictive. Many embodiments will be apparentto those of skill in the art upon reading the above description. Thescope of the invention should, therefore, be determined not withreference to the above description, but should instead be determinedwith reference to the appended claims, along with the full scope ofequivalents to which such claims are entitled. The disclosures of allarticles and references, including patent applications and publications,are incorporated herein by reference for all purposes.

What is claimed is:
 1. A method for preparing an R,S-halomethyl alcohol(R,S-HMA) compound having the following general formula:

said method comprising: reducing a halomethyl ketone (HMK) compoundhaving the following general formula:

with a non-chelating, bulky reducing agent to form said R,S-HMAcompound; wherein: R¹ is an amino acid side chain; R² is a blockinggroup; and X¹ is a leaving group.
 2. The method in accordance with claim1,wherein said non-chelating, bulky reducing agent is a member selectedfrom the group consisting of lithium aluminum t-butoxyhydride (LATBH)and sodium tris-t-butoxyborohydride (STBH).
 3. The method in accordancewith claim 1, wherein said non-chelating, bulky reducing agent islithium aluminum t-butoxyhydride (LATBH).
 4. The method in accordancewith claim 1, wherein R¹ is a member selected from the group consistingof a benzyl group, an S-phenyl group, an alkyl group andpara-nitrobenzene.
 5. The method in accordance with claim 1, wherein X¹is a halogen.
 6. The method in accordance with claim 5, wherein X¹ ischloro or bromo.
 7. The method in accordance with claim 1, wherein R² isa blocking group selected from the group consisting of BOC, MOC and CBZ.8. The method in accordance with claim 1, wherein the reduction iscarried out in a solvent selected from the group consisting of diethylether, THF, MTBE, glyme and diglyme.
 9. The method in accordance withclaim 8, wherein said solvent is diethyl ether.
 10. The method inaccordance with claim 1, wherein the reduction is carried out at atemperature ranging from about −30° C. to about 25° C.
 11. The method inaccordance with claim 1, wherein the reduction is carried out at atemperature ranging from about −5° C. to about 5° C.
 12. A method forpreparing an R,S-halomethyl alcohol (R,S-HMA) compound having thefollowing general formula:

said method comprising: reducing a halomethyl ketone (HMK) compoundhaving the following general formula:

with lithium aluminum t-butoxyhydride (LATBH) to form said R,S-HMAcompound; wherein: R¹ is an amino acid side chain; R² is a blockinggroup; and X¹ is a leaving group.
 13. The method in accordance withclaim 12, wherein R¹ is a member selected from the group consisting of abenzyl group, an S-phenyl group, an alkyl group and para-nitrobenzene.14. The method in accordance with claim 12, wherein X¹ is chloro. 15.The method in accordance with claim 12, wherein R² is a blocking groupselected from the group consisting of BOC, MOC and CBZ.
 16. The methodin accordance with claim 12, wherein the reduction is carried out indiethyl ether and at a temperature ranging from about −5° C. to about 5°C.
 17. A method for preparing an R,S-halomethyl alcohol (R,S-HMA)compound having the following general formula:

said method comprising: reducing a halomethyl ketone (HMK) compoundhaving the following general formula:

with a reducing agent selected from the group consisting of sodiumcyanoborohydride, cerium chloride/sodium borohydride, K-Selectride®,KS-Selectride® and (+)-Dip Chloride™ to form said R,S-HMA compound;wherein: R¹ is an amino acid side chain; R² is a blocking group; and X¹is a leaving group.
 18. A method for isolating an R,S-halomethyl alcohol(R,S-HMA) from a mixture of R,S- and S,S-HMAs, said method comprising:combining the mixture of R,S- and S,S-HMAs with hexane and heating to atemperature ranging from 50° C. to about 60° C. to produce a hexaneextractant; cooling said hexane extractant to a temperature ranging fromabout 0° C. to about 10° C., filtering said hexane extractant to form afirst retentate and recovering said first retentate; combining saidfirst retentate with hexane to form a hexane solution, heating saidhexane solution to a temperature ranging from about 50° C. to about 60°C., and cooling said hexane solution to a temperature ranging from about30° C. to about 40° C. to produce a suspension; and filtering saidsuspension to form a second retentate and recovering said secondretentate, wherein said R,S-HMA is present in said second retentate. 19.A method for preparing an R,S-epoxide compound having the followinggeneral formula:

said method comprising: reducing a halomethyl ketone (HMK) compoundhaving the following general formula:

with a non-chelating, bulky reducing agent to form an R,S-halomethylalcohol (R,S-HMA) compound having the following general formula:

and contacting said R,S-HMA compound of Formula II with an alkali metalbase to form said R,S-epoxide compound; wherein: R¹ is an amino acidside chain; R² is a blocking group; and X¹ is a leaving group.
 20. Themethod in accordance with claim 19, wherein R¹ is a benzyl group; R² isa BOC blocking group; and X¹ is chloro or bromo.
 21. The method inaccordance with 19, wherein said non-chelating, bulky reducing agent isa member selected from the group consisting of lithium aluminumt-butoxyhydride (LATBH) and sodium tris-t-butoxyborohydride (STBH). 22.The method in accordance with claim 19, wherein the reduction is carriedout in diethyl ether.
 23. The method in accordance with claim 19,wherein said alkali metal base is a member selected from the groupconsisting of NaOH, KOH, LiOH, NaOCH₃, NaOCH₂CH₃ and KOtBu.
 24. A methodfor preparing an R,S-epoxide compound having the following generalformula:

said method comprising: (a) reducing a halomethyl ketone (HMK) compoundhaving the following general formula:

 with a reducing agent to form an S,S-halomethyl alcohol (S,S-HMA)compound having the following general formula:

(b) contacting said S,S-HMA compound of Formula II with a memberselected from the group consisting of arylsulfonyl halides andalkylsulfonyl halides in the presence of an amine to form anS,S-halomethyl sulfonyl (S,S-HMS) compound having the following generalformula:

(c) contacting said S,S-HMS compound of Formula III with an acetate inthe presence of a phase transfer catalyst and water to form anR,S-halomethyl acetate (R,S-HMAc) compound having the following generalformula:

and (d) contacting said R,S-HMAc compound of Formula IV with an alkalimetal base to form said R,S-epoxide; wherein: R¹ is an amino acid sidechain; R² is a blocking group; R³ is a member selected from the groupconsisting of arylsulfonyls and alkylsulfonyls; R⁴ is an acyl group; andX¹ is a leaving group.
 25. The method in accordance with claim 24,wherein R¹ is a benzyl group; R² is a BOC blocking group; and X¹ ischloro or bromo.
 26. The method in accordance with claim 24, wherein R³is a member selected from the group consisting of methylsulfonyl,toluenesulfonyl, trifluoromethanesulfonyl and para-nitrobenzenesulfonyl.27. The method in accordance with claim 24, wherein R⁴ is an acetylgroup.
 28. The method in accordance with claim 24, wherein said reducingagent is a member selected from the group consisting of sodiumborohydride, lithium aluminum hydride and sodium cyanoborohydride. 29.The method in accordance with claim 24, wherein step (a) is carried outin a solvent selected from the group consisting of ethanol, methanol,isopropanol, THF and diethyl ether.
 30. The method in accordance withclaim 24, wherein step (a) is carried out at a temperature ranging fromabout −30° C. to about room temperature.
 31. The method in accordancewith claim 24, wherein said amine is triethylamine.
 32. The method inaccordance with claim 24, wherein step (b) is carried out in a solventselected from the group consisting of chlorinated solvents, ethylacetate, ethers and aromatic hydrocarbons.
 33. The method in accordancewith claim 24, wherein step (b) is carried out in toluene.
 34. Themethod in accordance with claim 24, wherein step (b) is carried out at atemperature ranging from about −30° C. to about 100° C.
 35. The methodin accordance with claim 24, wherein step (b) is carried out at atemperature ranging from about 10° C. to about 70° C.
 36. The method inaccordance with claim 24, wherein said acetate is a member selected fromthe group consisting of cesium acetate, potassium acetate,tetrabutylammonium acetate and sodium acetate.
 37. The method inaccordance with claim 24, wherein step (c) is carried out at atemperature ranging from about 20° C. to about 100° C.
 38. The method inaccordance with claim 24, wherein step (c) is carried out at atemperature ranging from about 65° C. to about 75° C.
 39. The method inaccordance with claim 24, wherein step (c) is carried out in a solventselected from the group consisting of hydrocarbons, aromatichydrocarbons and chlorinated solvents.
 40. The method in accordance withclaim 24, wherein step (c) is carried out in toluene.
 41. The method inaccordance with claim 24, wherein said phase transfer catalyst is amember selected from the group consisting of crown ethers, quaternaryammonium salts and quaternary phosphonium salts.
 42. The method inaccordance with claim 24, wherein said phase transfer catalyst is acrown ether.
 43. The method in accordance with claim 24, wherein saidcrown ether is 18-crown-6.
 44. The method in accordance with claim 24,wherein said water is present in an amount ranging from about 0.5% toabout 10%.
 45. The method in accordance with claim 24, wherein saidwater is present in an amount ranging from about 0.5% to about 5%. 46.The method in accordance with claim 24, wherein said alkali metal baseis a member selected from the group consisting of NaOH, KOH, LiOH,NaOCH₃, NaOCH₂CH₃ and KOtBu.
 47. The method in accordance with claim 24,wherein said (d) is carried out in a solvent selected from the groupconsisting of hydrocarbons, aromatic hydrocarbons, chlorinated solventsand THF.
 48. The method in accordance with claim 47, wherein saidsolvent is a mixture of toluene and THF.
 49. The method in accordancewith claim 24, further comprising purifying said R,S-epoxide compound byrecrystallization with petroleum ether.
 50. A method for preparing anS,S-halomethyl alcohol (S,S-HMA) compound having the following generalformula:

said method comprising: reducing an S,S-halomethyl ketone (S,S-HMK)compound having the following general formula:

with a reducing agent selected from the group consisting of sodiumborohydride, lithium aluminum hydride and sodium cyanoborohydride toform said S,S-HMA compound; wherein: R¹ is an amino acid side chain; R²is a blocking group; and X¹ is a leaving group.
 51. The method inaccordance with claim 50, wherein said reducing is carried out in asolvent selected from the group consisting of ethanol, methanol,isopropanol, THF and diethyl ether.
 52. A method for preparing anS,S-halomethyl sulfonyl (S,S-HMS) compound having the following formula:

said method comprising: contacting an S,S-halomethyl alcohol (S,S-HMA)compound having the following general formula:

with a member selected from the group consisting of arylsulfonyl halidesand alkylsulfonyl halides to form said S,S-HMS compound; wherein: R¹ isan amino acid side chain; R² is a blocking group; R³ is a memberselected from the group consisting of arylsulfonyls and alkylsulfonyls;and X¹ is a leaving group.
 53. The method in accordance with claim 52,wherein said contacting is carried out in toluene.
 54. The method inaccordance with claim 52, wherein said contacting is carried out at atemperature ranging from about 5° C. to about 10° C.
 55. A method forpreparing an R,S-halomethyl acetate (R,S-HMAc) compound having thefollowing general formula:

contacting an S,S-halomethyl sulfonyl (S,S-HMS) compound having thefollowing general formula:

with an acetate in the presence of a phase transfer catalyst and waterto form said R,S-HMAc compound; wherein: R¹ is an amino acid side chain;R² is a blocking group; R³ is a member selected from the groupconsisting of arylsulfonyls and alkylsulfonyls; R⁴ is an acyl group; andX¹ is a leaving group.
 56. The method in accordance with claim 55,wherein said acetate is a member selected from the group consisting ofcesium acetate, potassium acetate, tetrabutylammonium acetate and sodiumacetate
 57. The method in accordance with claim 55, wherein said phasetransfer catalyst is a crown ether.
 58. The method in accordance withclaim 55, wherein said crown ether is 18-crown-6.
 59. The method inaccordance with claim 55, wherein said water is present in an amountranging from about 1% to about 2%.
 60. A method for preparing anR,S-epoxide compound having the following general formula:

said method comprising: contacting an R,S-halomethyl acetate (R,S-HMAc)compound having the following general formula:

with an alkali metal base to form said R,S-epoxide; wherein: R¹ is anamino acid side chain; R² is a blocking group; R⁴ is an acyl group; andX¹ is a leaving group.
 61. The method in accordance with claim 60,wherein said alkali metal base is a member selected from the groupconsisting of NaOH, KOH, LiOH, NaOCH₃, NaOCH₂CH₃ and KOtBu.
 62. Themethod in accordance with claim 60, wherein said contacting is carriedout in a solvent that is a mixture of toluene and THF.
 63. A method forpreparing an R,S-epoxide compound having the following general formula:

said method comprising: (a) contacting an S,S-halomethyl sulfonyl(S,S-HMS) compound having the following general formula:

 with a carbamate-forming acetate to form a cyclic carbamate having thefollowing general formula:

and (b) contacting said cyclic carbamate with an alkali metal base toform said R,S-epoxide; wherein: R¹ is an amino acid side chain; R² is ablocking group; R³ is a member selected from the group consisting ofarylsulfonyls and alkylsulfonyls; and X¹ is a leaving group.
 64. Themethod in accordance with claim 63, wherein R³ is a member selected fromthe group consisting of methylsulfonyl and toluenesulfonyl.
 65. Themethod in accordance with claim 63, wherein said carbamate-formingacetate is a member selected from the group consisting of sodiumtrichloroacetate, potassium trichloroacetate, tetrabutylammoniumtrichloroacetate, sodium tribromoacetate, potassium tribromoacetatesodium trifluoroacetate and potassium trifluoroacetate
 66. The method inaccordance with claim 63, wherein said carbamate-forming acetate issodium trichloroacetate.
 67. The method in accordance with claim 63,wherein step (a) is carried out in toluene
 68. The method in accordancewith claim 63, wherein said alkali metal base is a member selected fromthe group consisting of NaOH, KOH, LiOH, NaOCH₃, NaOCH₂CH₃ and KOtBu.69. A cyclic carbamate compound having the following general formula:

wherein: R¹ is an amino acid side chain; R² is hydrogen or a blockinggroup; R³ is a member selected from the group consisting ofarylsulfonyls and alkylsulfonyls; and X¹ is a leaving group.
 70. Amethod for preparing an alkene having the following general formula:

said method comprising: (a) contacting a compound having the followinggeneral formula:

 with a hydrohalo acid to form a compound having the following generalformula:

(b) reducing a compound of Formula II with a reducing agent to form acompound having the following general formula:

and (c) dehalohydroxylating a compound of Formula III to form saidalkene; wherein: R¹ is an amino acid side chain; R² is a blocking group;and X¹ is a halo group.
 71. The method in accordance with claim 70,wherein said hydrohalo acid is a member selected from the groupconsisting of hydrobromic acid, hydrochloric acid and hydroiodic acid.72. The method in accordance with claim 70, wherein said hydrohalo acidis hydrobromic acid or hydrochloric acid.
 73. The method in accordancewith claim 70, wherein step (c) is carried out using a member selectedfrom the group consisting of zinc metal, nickel metal and zinc mercuryamalgan.
 74. The method in accordance with claim 70, wherein step (c) iscarried out in a solvent selected from the group consisting of methanol,ethanol,.isopropanol, THF, MTBE and toluene.
 75. The method inaccordance with claim 70, wherein step (c) is carried out using zincdust in ethanol.